resiniferatoxin and 4-methylcatechol

Neuropathic pain in small-fiber neuropathy results from injury to and sensitization of nociceptors. Functional prostatic acid phosphatase (PAP) acts as an analgesic effector. However, the mechanism responsible for the modulation of PAP neuropathology, which leads to loss of the analgesic effect after small-fiber neuropathy, remains unclear.. We used a resiniferatoxin (RTX)-induced small-fiber neuropathy model to examine whether functional PAP(þ) neurons are essential to maintain the analgesic effect. PAP(þ) neurons were categorized into small to medium neurons (25th-75th percentile: 17.1-23.7 mm); these neurons were slightly reduced by RTX (p¼0.0003). By contrast, RTX-induced activating transcription factor 3 (ATF3), an injury marker, in PAP(þ) neurons (29.0%5.6% vs. 0.2%0.2%, p¼0.0043), indicating PAP neuropathology. Moreover, the high-affinity nerve growth factor (NGF) receptor (trkA) colocalized with PAP and showed similar profiles after RTX-induced neuropathy, and the PAP/trkA ratios correlated with the degree of mechanical allodynia (r¼0.62, p¼0.0062). The NGF inducer 4-methylcatechol (4MC) normalized the analgesic effects of PAP; specifically, it reversed the PAP and trkA profiles and relieved mechanical allodynia. Administering 2.5S NGF showed similar results to those of administering 4MC. This finding suggests that the analgesic effect of functional PAP is mediated by NGF-trkA signaling, which was confirmed by NGF neutralization.. This study revealed that functional PAP(þ) neurons are essential for the analgesic effect, which is mediated by NGF-trkA signaling.

Topics: Acid Phosphatase; Analgesics; Animals; Catechols; Diterpenes; Hyperalgesia; Mice; Models, Biological; Nerve Growth Factor; Neuralgia; Neurons; Phenotype; Receptor, trkA; Receptors, Purinergic P2X3; Signal Transduction

To investigate whether 4-methylcatechol (4MC) could decrease the duration of the thermosensation disorder and promote the innervation of peptidergic intraepidermal nerve fibers (IENFs), we developed a resiniferatoxin (RTX)-induced neuropathic mouse model with thermal analgesia and skin denervation that was followed by daily 4MC treatment. On day 7 after RTX administration (RTXd7), the substance P (SP)(+) IENFs were completely depleted compared with the vehicle group (p < 0.0001), whereas the calcitonin gene-related peptide (CGRP)(+) IENFs were dramatically, but not completely, depleted (p < 0.0001). While SP(+) IENFs remained depleted (p = 0.0043), CGRP(+) IENFs were recovered by RTXd84 (p = 0.78). 4MC had no effect on the reinnervation of SP(+) IENFs, but markedly promoted the reinnervation of CGRP(+) IENFs on RTXd35 (p = 0.035). On RTXd56, CGRP(+) IENFs were comparable with the vehicle group (p = 0.39). In addition, 4MC normalized thermal analgesia on RTXd35 compared with RTX group (p = 0.007). In the current study, the significant promotion of reinnervation of CGRP(+) IENFs and thermal latencies on RTXd35 by 4MC indicated that CGRP(+) IENFs were responsible for the thermal transmission in chronic phase of RTX-induced neuropathy.

Topics: Analgesia; Animals; Catechols; Denervation; Disease Models, Animal; Diterpenes; Hot Temperature; Male; Mice; Nerve Regeneration; Neuroprotective Agents; Neurotoxins; Pain Threshold; Skin

To generate an experimental neuropathy model in which small-diameter sensory nerves are specifically affected and to test a potential treatment, adult mice were given a single injection (50 microg/kg, i.p.) of the capsaicin analog resiniferatoxin (RTX). On Day 7 after RTX treatment, there was a 53% reduction in unmyelinated nerve density in the medial plantar nerve (p = 0.0067) and a 66% reduction in epidermal nerve density of hind paw skin (p = 0.0004) compared with vehicle-treated controls. Substance P-immunoreactive dorsal root ganglion neurons were also markedly depleted (p = 0.0001). These effects were associated with the functional deficit of prolonged withdrawal latencies to heat stimuli (p = 0.0007) on a hot plate test. The potential therapeutic effects of 4-methylcatechol (4MC) on this neuropathy were then tested by daily injections of 4MC (10 microg/kg, i.p.) from Days 7 to 35 after neuropathy induction. On Day 35, 4MC-treated mice had an increase in unmyelinated (p = 0.014) and epidermal nerve (p = 0.0013) densities and a reduction in thermal withdrawal latency (p = 0.0091) compared with RTX-only controls. These results indicate that 4MC promoted regeneration of unmyelinated nerves in experimental RTX-induced neuropathy and enhanced function.

Topics: Animals; Calcitonin Gene-Related Peptide; Capsaicin; Catechols; Disease Models, Animal; Diterpenes; Drug Interactions; Ganglia, Spinal; Hyperalgesia; Male; Mice; Mice, Inbred ICR; Nerve Fibers, Unmyelinated; Nerve Regeneration; Neural Conduction; Neuroprotective Agents; Peripheral Nervous System Diseases; Reaction Time; Skin; Substance P; Ubiquitin Thiolesterase